chr1-1214100-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003327.4(TNFRSF4):c.28C>T(p.Arg10Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,585,918 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R10H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0080 ( 95 hom. )

Consequence

TNFRSF4
NM_003327.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.340

Publications

10 publications found

Variant links:

Genes affected

TNFRSF4 (HGNC:11918): (TNF receptor superfamily member 4) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to activate NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. Knockout studies in mice suggested that this receptor promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. The knockout studies also suggested the roles of this receptor in CD4+ T cell response, as well as in T cell-dependent B cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

TNFRSF4 Gene-Disease associations (from GenCC):

combined immunodeficiency due to OX40 deficiency
Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

TNFRSF4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057964325).

BP6

Variant 1-1214100-G-A is Benign according to our data. Variant chr1-1214100-G-A is described in ClinVar as Benign. ClinVar VariationId is 474794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00527 (803/152330) while in subpopulation SAS AF = 0.0193 (93/4822). AF 95% confidence interval is 0.0161. There are 5 homozygotes in GnomAd4. There are 388 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF4	NM_003327.4 link	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 7	ENST00000379236.4	NP_003318.1	P43489
TNFRSF4	NM_001410709.1 link	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 6		NP_001397638.1
TNFRSF4	XR_007063145.1 link	n.54C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF4	ENST00000379236.4 link	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 7	1	NM_003327.4	ENSP00000368538.3		P43489

Frequencies

GnomAD3 genomes

AF:

0.00529

AC:

805

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00562

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.00396

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00679

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.00854

AC:

1757

AN:

205672

AF XY:

0.00985

show subpopulations

Gnomad AFR exome

AF:

0.00206

Gnomad AMR exome

AF:

0.00352

Gnomad ASJ exome

AF:

0.00848

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00511

Gnomad NFE exome

AF:

0.00796

Gnomad OTH exome

AF:

0.00841

GnomAD4 exome

AF:

0.00799

AC:

11452

AN:

1433588

Hom.:

Cov.:

AF XY:

0.00846

AC XY:

6023

AN XY:

711812

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

33038

American (AMR)

AF:

0.00335

AC:

141

AN:

42130

Ashkenazi Jewish (ASJ)

AF:

0.00929

AC:

239

AN:

25720

East Asian (EAS)

AF:

0.0000514

AC:

AN:

38874

South Asian (SAS)

AF:

0.0244

AC:

2035

AN:

83548

European-Finnish (FIN)

AF:

0.00580

AC:

251

AN:

43312

Middle Eastern (MID)

AF:

0.0213

AC:

AN:

4234

European-Non Finnish (NFE)

AF:

0.00736

AC:

8120

AN:

1103394

Other (OTH)

AF:

0.00881

AC:

523

AN:

59338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

663

1326

1989

2652

3315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

320

640

960

1280

1600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00527

AC:

803

AN:

152330

Hom.:

Cov.:

AF XY:

0.00521

AC XY:

388

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

41582

American (AMR)

AF:

0.00562

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0193

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00396

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00678

AC:

461

AN:

68018

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00712

Hom.:

Bravo

AF:

0.00500

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00116

AC:

ESP6500EA

AF:

0.00736

AC:

ExAC

AF:

0.00785

AC:

932

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency due to OX40 deficiency

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

TNFRSF4-related disorder

Benign:1

Oct 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.90

PhyloP100

-0.34

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.12

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.011

Polyphen

0.98

Vest4

0.16

MVP

0.62

MPC

0.20

ClinPred

0.016

GERP RS

2.2

PromoterAI

-0.058

Neutral

(source)

Varity_R

0.17

gMVP

0.84

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over